Schizophrenia is a severe, debilitating psychiatric disorder of unknown cause. I hypothesize that some cases of schizophrenia are caused by individually rare, often de novo, highly penetrant mutations. Sporadic cases of schizophrenia occurring in previously unaffected families may be most likely to harbor such mutations. Potentially unstable oligonucleotide repeats are among genomic features most vulnerable to such mutations. Repeat expansions are potentially intriguing in schizophrenia given the disorder's neurological phenotype, paternal age bias, and possible anticipation. The purpose of this project is to identify pathogenic repeat expansions with large effect on the development of schizophrenia. Using a bioinformatics search, I have identified 327 tri-, tetra-, or pentanucleotide repeats that overlap transcribed features (i.e. coding genes or noncoding RNAs) and are sufficiently long to likely be polymorphic. By screening genomic DNA from individuals with sporadic schizophrenia, I will identify repeats with more apparent homozygotes than expected based on Hardy-Weinberg equilibrium (HWE) criteria. To exclude loss of heterozygosity due to technical artifacts, I will genotype repeats that fail HWE, using multiple primer pairs, in cases and ancestry-matched controls. In preliminary experiments, I have identified a repeat with a two-fold excess of homozygosity among cases but perfect fit to HWE among controls. This excess is observed with multiple non-overlapping primer pairs and after identifying short repeats by capillary electrophoresis and medium length repeats by long-range PCR. Next I will screen cases and controls at this locus by Southern blot to identify any expansions >300 repeats and any deletions of the entire repeat. I will evaluate repeats elsewhere in the genome in the same way. If either large expansions or deletions are observed at any repeat, I will undertake preliminary experimental characterization of the mutations. I will also sequence genes harboring interesting repeats in all cases to identify mutations other than repeat expansions;e.g. frameshifts or point mutations. The goal of NIMH is to reduce the burden of mental illness through research. This study aims to identify genetic contributors to schizophrenia, which will hopefully lead to better diagnostic testing and treatment for individuals with the disorder.